Methods of making and using N-desmethylzopiclone

ABSTRACT

The invention is directed to compositions comprising, and methods of using, racemic N-desmethylzopiclone, optically pure (+)-N-desmethylzopiclone, and optically pure (-)-N-desmethylzopiclone in the treatment and prevention of diseases and conditions in mammals. The invention is further directed to novel methods of preparing N-desmethylzopiclone, optically pure (+)-N-desmethylzopiclone, and optically pure (-)-N-desmethylzopiclone.

This application is divisional of Ser. No. 09/548,607 filed Apr. 13,2000, now patented U.S. Pat. No. 6,339,086 which claims benefit of Ser.No. 60/134,239 filed May 4, 1999 and claims benefit of Ser. No.60/135,037 filed May 20, 1999.

FIELD OF THE INVENTION

The invention relates to compositions and methods for the treatment andprevention of anxiety, convulsive disorders, and other disorders.

BACKGROUND OF THE INVENTION

Zopiclone, chemically named(±)-6-(5-chloro-2-pyridinyl)-6,7-dihydro-7-oxo-5H-pyrrolo-[3,4b]pyrazin-5-yl-4-methylpiperazine-1-carboxylate,is a non-benzodiazepine hypnotic which has the following structure:

Zopiclone and some of its uses are described by U.S. Pat. Nos. 3,862,149and 4,220,646. Uses of the optically pure (+) and (−) enantiomers of thedrug (i.e., (+)-zopiclone and (−)-zopiclone) are described by U.S. Pat.No. 5,786,357 and WO 93/10788, respectively.

Zopiclone binds at or near benzodiazepine receptor complexes. Goa, K. L.and Heel, R. C. Drugs, 32:48-65 (1986). These complexes are located bothwithin the central nervous system and peripherally (e.g., in theendocrine system), and contain macromolecular complexes which comprisebenzodiazepine and GABA binding sites. Verma, A. and Snyder, S. H.,Annu. Rev. Pharmacol. Toxicol. 29:307-22 (1989). Benzodiazepine receptorcomplexes are further associated with, and interact with, membranechannels for chloride ion transport. Upon binding to a benzodiazepinereceptor complex, zopiclone is believed to allosterically modulate theactivity of the complex by increasing trans-membrane conductance ofchloride ions. This stabilizes neuronal membrane potentials and dampensexcitatory input. See Meldrum, B. S., Brit. J. Clin. Pharm. 27(suppl.1):3S-11S (1989); Goodman & Gilman's The Pharmacological Basis ofTherapeutics, Hardman, J. G., et al., eds. p. 365 (9^(th) ed., 1996).

Although chemically unrelated to the benzodiazepines, zopiclonepossesses a spectrum of activity analogous to that of thebenzodiazepines. Goa, K.L. and Heel, R. C. Drugs, 32:48-65, (1986).Zopiclone and its optically pure enantiomers are reportedly useful inthe treatment of diseases and conditions including, but not limited to,epilepsy, anxiety, aggressive behavior, muscle tension, behavioraldisorders, depression, schizophrenia, and endocrine disorders. See,e.g., WO 93/10787. Racemic zopiclone has been used to improve sleep inadults and geriatric patients with several types of sleep disordersincluding situational, transient primary and secondary insomnia. See,e.g., Brun, J. P., Pharm. Biochem. Behav. 29:831-832 (1988).

Some compounds which bind at benzodiazepine receptors can also haveaffinity for muscarinic receptors such as acetylcholine receptors.Julou, L., et al., Pharmacol. Biochem. Behav. 23:653-659 (1985).Consequently, administration of such compounds can result in adverseeffects caused by muscarinic agonists and antagonists. Such adverseeffects include, but are not limited to, drymouth, thirst, slowing andacceleration of the heart, dilated pupils, blurred vision, restlessness,fatigue, headache, hallucinations and delirium. Goodman & Gilman's ThePharmacological Basis of Therapeutics, Hardman, J. G., et al., eds. p.142 (9^(th) ed., 1996).

The metabolism of zopiclone is rapid and complex. When administeredorally to healthy humans, the racemic drug is extensively metabolized byat least three major pathways, as shown below in Scheme 1.

Metabolic pathways include oxidation, hydrolysis, and demethylation. Anoxidation pathway produces N-oxidezopiclone, a metabolite which isreportedly less active than zopiclone and reportedly accounts for 11% ofan oral dose of racemic zopiclone. A hydrolysis pathway produces analcohol which is reportedly biologically inactive. A demethylationmetabolic pathway produces N-desmethylzopiclone, a metabolite whichreportedly accounts for 15% of an oral dose of racemic zopiclone, andwhich is also reportedly inactive. Goa, K. L. and Heel, R. C. Drugs,32:48-65, (1986). Additional metabolites are formed from each of thethree pathways shown in Scheme 1.

The full pharmacological activity of zopiclone is reportedly due to thedrug itself and the N-oxide metabolite (i.e., N-oxidezopiclone). Id.Unfortunately, the single-dose elimination half-lives of both of thesecompounds after administration of racemic zopiclone range from onlyabout 3.5 to about 6 hours, which limits the usefulness of zopiclone inthe treatment of a wide number of disorders. For example, the rapidelimination of zopiclone and N-oxidezopiclone limits their usefulness inlong-term anxiolytic treatment. The single-dose elimination half-life ofthe reportedly inactive N-desmethyl-zopiclone metabolite (hereinreferred to as “N-desmethylzopiclone”) after administration of racemiczopiclone is between about 7 and about 11 hours in healthy subjects. Id.

Racemic zopiclone possesses further disadvantages, in particular, itcauses adverse side effects which include, but are not limited to, thedevelopment of a bitter taste due to salivary secretion of the drug, drymouth, heart palpitations, drowsiness, morning tiredness, headache,dizziness, impairment of psychomotor skills and related effects. Acompound is thus desired for the treatment or prevention of variousdisorders which does not possesses disadvantages associated with racemiczopiclone.

SUMMARY OF THE INVENTION

The invention is directed to compositions comprising, and methods ofusing, racemic N-desmethylzopiclone ((±)-N-desmethylzopiclone),optically pure (+)-N-desmethylzopiclone, and optically pure(−)-N-desmethylzopiclone in the treatment and prevention of diseases andconditions in mammals.

One embodiment of the invention encompasses a method of treating orpreventing anxiety in a patient which comprises administering to apatient in need of such treatment or prevention a therapeuticallyeffective amount of N-desmethylzopiclone or a pharmaceuticallyacceptable salt, solvate, hydrate, or clathrate thereof. One method ofthis embodiment is the treatment or prevention of acute anxiety. Anothermethod of this embodiment is the treatment or prevention of chronicanxiety. Yet another method of this embodiment is the treatment orprevention of general anxiety disorder. In a preferred method of thisembodiment, N-desmethylzopiclone is (+)-N-desmethylzopiclonesubstantially free of its (−) enantiomer.

Another embodiment of the invention encompasses a method of treating orpreventing a convulsive state in a patient which comprises administeringto a patient in need of such treatment or prevention a therapeuticallyeffective amount of N-desmethylzopiclone or a pharmaceuticallyacceptable salt, solvate, hydrate, or clathrate thereof. A particularmethod of this embodiment is the treatment or prevention of epilepsy orepileptic seizures. In a preferred method of this embodiment,N-desmethylzopiclone is (+)-N-desmethylzopiclone substantially free ofits (−) enantiomer.

Yet another embodiment of the invention encompasses a method of treatingor preventing an affective disorder in a patient which comprisesadministering to a patient in need of such treatment or prevention atherapeutically effective amount of N-desmethylzopiclone or apharmaceutically acceptable salt, solvate, hydrate, or clathratethereof. A particular method of this embodiment is the treatment orprevention of depression. Another method of this embodiment is thetreatment or prevention of attention deficit disorder or attentiondeficit disorder with hyperactivity. In a preferred method of thisembodiment, N-desmethylzopiclone is (+)-N-desmethylzopiclonesubstantially free of its (−) enantiomer.

A further embodiment of the invention encompasses a method of treatingor preventing a sleep disorder in a patient which comprisesadministering to a patient in need of such treatment or prevention atherapeutically effective amount of N-desmethylzopiclone or apharmaceutically acceptable salt, solvate, hydrate, or clathratethereof. A particular method of this embodiment is the treatment orprevention of insomnia. In a preferred method of this embodiment,N-desmethylzopiclone is (+)-N-desmethylzopiclone substantially free ofits (−) enantiomer.

Another embodiment of the invention encompasses a method of treating orpreventing aggressive behavior in a patient which comprisesadministering to a patient in need of such treatment or prevention atherapeutically effective amount of N-desmethylzopiclone or apharmaceutically acceptable salt, solvate, hydrate, or clathratethereof. In a preferred method of this embodiment, N-desmethylzopicloneis (+)-N-desmethylzopiclone substantially free of its (−) enantiomer.

Still another embodiment of the invention encompasses a method oftreating or preventing spasticity or acute muscle spasm spasticity in apatient which comprises administering to a patient in need of suchtreatment or prevention a therapeutically effective amount ofN-desmethylzopiclone or a pharmaceutically acceptable salt, solvate,hydrate, or clathrate thereof. In a preferred method of this embodiment,N-desmethylzopiclone is (+)-N-desmethylzopiclone substantially free ofits (−) enantiomer.

Yet another embodiment of the invention encompasses a method of treatingor preventing a behavioral disorder in a patient which comprisesadministering to a patient in need of such treatment or prevention atherapeutically effective amount of N-desmethylzopiclone or apharmaceutically acceptable salt, solvate, hydrate, or clathratethereof. In a preferred method of this embodiment, N-desmethylzopicloneis (+)-N-desmethylzopiclone substantially free of its (−) enantiomer.

Still another embodiment of the invention encompasses a method oftreating a schizophrenic disorder in a patient which comprisesadministering to a patient in need of such treatment or prevention atherapeutically effective amount of N-desmethylzopiclone or apharmaceutically acceptable salt, solvate, hydrate, or clathratethereof. In a preferred method of this embodiment, N-desmethylzopicloneis (+)-N-desmethylzopiclone substantially free of its (−) enantiomer.

Still another embodiment of the invention encompasses a method oftreating or preventing a disease or condition associated with abnormalplasma hormone levels in a patient which comprises administering to apatient in need of such treatment or prevention a therapeuticallyeffective amount of N-desmethylzopiclone or a pharmaceuticallyacceptable salt, solvate, hydrate, or clathrate thereof. In a particularmethod of this embodiment, the disorder is an endocrine disorder. In apreferred method of this embodiment, N-desmethylzopiclone is(+)-N-desmethylzopiclone substantially free of its (−) enantiomer.

Still another embodiment of the invention encompasses a method oftreating alcohol or drug addiction in a patient which comprisesadministering to a patient in need of such treatment a therapeuticallyeffective amount of N-desmethylzopiclone or a pharmaceuticallyacceptable salt, solvate, hydrate, or clathrate thereof. In a preferredmethod of this embodiment, N-desmethylzopiclone is(+)-N-desmethylzopiclone substantially free of its (−) enantiomer.

Still another embodiment of the invention encompasses a method oftreating or preventing drug withdrawal, alcohol withdrawal, symptoms ofdrug withdrawal, or symptoms of alcohol withdrawal in a patient whichcomprises administering to a patient in need of such treatment atherapeutically effective amount of N-desmethylzopiclone or apharmaceutically acceptable salt, solvate, hydrate, or clathratethereof. Examples of such symptoms are disclosed herein. In a preferredmethod of this embodiment, N-desmethylzopiclone is(+)-N-desmethylzopiclone substantially free of its (−) enantiomer.

Patients who may receive the therapeutic or prophylactic benefits of themethods of the invention include those suffering from the diseases orconditions described above, as well as patients suffering from cancer,patients currently being treated with a muscarinic antagonist or amuscarinic agonist, and patients who are susceptible to adverse effectsassociated with racemic zopiclone.

A further embodiment of the invention encompasses pharmaceuticalcompositions comprising N-desmethylzopiclone, or a pharmaceuticallyacceptable salt, solvate, hydrate, or clathrate thereof. In preferredpharmaceutical compositions, N-desmethylzopiclone is(+)-N-desmethylzopiclone substantially free of its (−) enantiomer.Typical pharmaceutical compositions of the invention will compriseN-desmethylzopiclone and a pharmaceutically acceptable carrier. In oneembodiment, the pharmaceutical compositions of the present invention arefree of lactose (lactose-free), or other mono- or disaccharides. Inanother alternative embodiment, pharmaceutical compositions of theinvention are anhydrous or anhydrous and lactose-free.

Also encompassed by the invention are single unit dosage forms ofracemic and optically pure enantiomers of N-desmethylzopiclone, orpharmaceutically acceptable salts, solvates, hydrate, or clathratesthereof. Single unit dosage forms of the invention are suitable fororal, mucosal (e.g., nasal, sublingual, vaginal, buccal, or rectal),parenteral (e.g., subcutaneous, intravenous, bolus injection,intramuscular, or intraarterial), or transdermal administration.Preferred single unit dosage forms of racemic and optically pure (+)- or(−)-N-desmethylzopiclone are suitable for oral administration. Mostpreferred single unit dosage forms of racemic and optically pure (+)- or(−)-N-desmethylzopiclone are tablets, capsules and caplets.

Another embodiment of the invention encompasses methods of preparingoptically pure enantiomers of N-desmethylzopiclone. One method comprisestreating an optically pure enantiomer of zopiclone with 1-chloroethylchloroformate. Another method comprises treating an optically pureenantiomer of zopiclone with an azodicarboxylate, and hydrolyzing theresulting product under mild conditions. A preferred azodicarboxylate isdiethyl azodicarboxylate. Yet another method of this embodimentcomprises resolution of racemic desmethylzopiclone usingL-N-benzyloxycarbonyl phenylalanine (L-ZPA) as a resolution reagent.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to the synthesis, use, and pharmaceuticalcompositions of N-desmethylzopiclone which, until now, was believed topossess no pharmacological activity. The invention further relates tothe synthesis and use of optically pure (+)-N-desmethylzopiclone andoptically pure (−)-N-desmethylzopiclone. A general aspect of theinvention encompasses the use of (±)-N-desmethylzopiclone or opticallypure enantiomers of N-desmethylzopiclone to treat or prevent diseasesand conditions which are affected by the modulation of one or morecentral or peripheral benzodiazepine receptors.

Surprisingly, N-desmethylzopiclone, which has been reported to bepharmacologically inactive, is in fact a benzodiazepine receptoragonist. In addition, racemic and optically pure N-desmethylzopicloneonly weakly antagonize muscarinic receptors. Thus, racemicN-desmethylzopiclone or an optically pure enantiomer ofN-desmethylzopiclone may be used in the treatment or prevention of adisease or condition which is affected by the modulation of one or morebenzodiazepine receptors. Further, racemic and optically pureenantiomers of N-desmethylzopiclone may be used in the treatment orprevention of such diseases and conditions while avoiding longsingle-dose elimination half-life and adverse effects associated withracemic zopiclone. Further still, racemic and optically pure enantiomersof N-desmethylzopiclone may be used in the treatment or prevention ofsuch diseases and conditions while avoiding adverse effects associatedwith muscarinic receptor antagonists.

As used herein, the terms “mammal” and “patient” are usedinterchangeably, and include human.

The term “substantially free of its (−) enantiomer,” as used herein,means that the composition contains a significantly greater proportionof the (+) enantiomer of N-desmethylzopiclone in relation to the (−)enantiomer of N-desmethylzopiclone. In a preferred embodiment of thepresent invention the term “substantially free of its (−) enantiomer,”as used herein, means that the composition contains at least about 90%by weight of (+)-N-desmethylzopiclone and about 10% by weight or less of(−)-N-desmethylzopiclone. In a more preferred embodiment of the presentinvention, the term “substantially free of its (−) enantiomer,” as usedherein, means that the composition contains at least about 95% by weightof (+)-N-desmethylzopiclone and about 5% by weight or less of (−)N-desmethylzopiclone. In the most preferred embodiment, the term“substantially free of its (−) enantiomer,” as used herein, means thatthe composition contains at least about 99% by weight of(+)-N-desmethylzopiclone and about 1% or less of(−)-N-desmethylzopiclone. In another preferred embodiment, the term“substantially free of its (−) enantiomer,” as used herein, means thatthe composition contains nearly 100% by weight of the (+) isomer ofN-desmethylzopiclone. The above percentages are based on the totalamount of N-desmethylzopiclone present in the composition. The terms“substantially optically pure (+)-N-desmethylzopiclone,” “optically pure(+)-N-desmethylzopiclone” and “(+) isomer of N-desmethylzopiclone” arealso encompassed by the above described amounts.

The term “substantially free of its (+) enantiomer,” as used herein,means that the composition contains a significantly greater proportionof the (−) enantiomer of N-desmethylzopiclone in relation to the (+)enantiomer of N-desmethylzopiclone. In a preferred embodiment of thepresent invention the term “substantially free of its (+) enantiomer,”as used herein, means that the composition contains at least about 90%by weight of (−)-N-desmethylzopiclone and about 10% by weight or less of(+)-N-desmethylzopiclone. In a more preferred embodiment of the presentinvention the term “substantially free of its (+) enantiomer,” as usedherein, means that the composition contains at least about 95% by weightof (−)-N-desmethylzopiclone and about 5% by weight or less of(+)-N-desmethylzopiclone. In the most preferred embodiment, the term“substantially free of its (+) enantiomer,” as used herein, means thatthe composition contains at least about 99% by weight of(−)-N-desmethylzopiclone and about 1% or less of(+)-N-desmethylzopiclone. In another preferred embodiment, the term“substantially free of its (+) enantiomer,” as used herein, means thatthe composition contains nearly 100% by weight of the (−) isomer ofN-desmethylzopiclone. The above percentages are based on the totalamount of N-desmethylzopiclone present in the composition. The terms“substantially optically pure (−)-N-desmethylzopiclone,” “optically pure(−)-N-desmethylzopiclone” and “(−) isomer of N-desmethylzopiclone” arealso encompassed by the above described amounts.

As used herein, the term “pharmaceutically acceptable salt” refers tosalts prepared from pharmaceutically acceptable non-toxic acids,including inorganic acids and organic acids. Suitable non-toxic acidsinclude inorganic and organic acids such as acetic, alginic,anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric,ethenesulfonic, formic, fumaric, furoic, gluconic, glutamic, glucorenic,galacturonic, glycidic, hydrobromic, hydrochloric, isethionic, lactic,maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic,pantothenic, phenylacetic, propionic, phosphoric, salicylic, stearic,succinic, sulfanilic, sulfuric, tartaric acid, p-toluenesulfonic and thelike. Particularly preferred are hydrochloric, hydrobromic, phosphoric,and sulfuric acids, and most particularly preferred is the hydrochloridesalt.

As used herein, the term “benzodiazepine receptor agonist” means acompound that mimics the in vitro binding activity of a benzodiazepine(e.g., diazepam) to central or peripheral benzodiazepine receptors. Asused herein, a benzodiazepine receptor agonist may exhibit full orpartial agonistic effects as defined by Goodman & Gilman's ThePharmacological Basis of Therapeutics, Hardman, J. G., et al., eds. p.364 (9^(th) ed., 1996). Simply because a compound is referred to hereinas a “benzodiazepine receptor agonist,” however, does not imply that itexhibits a mechanism of action, a site of action, or an induced receptorconformational change identical to that of a benzodiazepine.

As used herein, the terms “diseases and conditions which are affected bythe modulation of one or more central or peripheral benzodiazepinereceptors,” “diseases and conditions which are affected by themodulation of one or more benzodiazepine receptors,” and “disease orcondition affected by the modulation of a benzodiazepine receptor” meana disease or condition that has at least one symptom which is mitigatedor alleviated by allosteric binding of a compound to benzodiazepinereceptors. Preferably, the at least one symptom is mitigated oralleviated by an increase in the trans-neuronal membrane chloridecurrent associated with the binding of only GABA to benzodiazepinereceptor complexes. Specific diseases and conditions which are affectedby the modulation of one or more benzodiazepine receptors include, butare not limited to: anxiety; affective disorders such as depression,attention deficit disorder (ADD), and attention deficit disorder withhyperactivity (ADDH) or attention deficit/hyperactivity disorder (ADHD);convulsive disorders such as epilepsy; aggressive behavior; spasticityor acute muscle spasm; behavioral disorders such as mood anxiety andschizophrenia; sleep disorders such as insomnia; alcohol and drugaddiction; and disorders associated with abnormal plasma hormone levelssuch as endocrine disorders.

As used herein, the terms “treating or preventing anxiety” and“treatment and prevention of anxiety” mean reducing the severity ofsymptoms associated with acute anxiety, chronic anxiety, general anxietydisorder caused by psychologic and/or physiologic factors, and otheranxiety disorders such as panic disorders, mood anxiety, panic attacks,phobias, obsessive-compulsive disorders, and post traumatic distressdisorder. Symptoms associated with acute anxiety include, but are notlimited to, a fear of losing control of one's own actions, a sense ofterror arising from no apparent reason, and a dread of catastrophe.Symptoms associated with chronic anxiety include, but are not limitedto, uneasiness, nervousness, nagging uncertainty about future events,headache, fatigue, and subacute autonomic symptoms.

As used herein, the terms “treating or preventing an affective disorder”and “treatment and prevention of an affective disorder” mean reducingthe severity of symptoms associated with a psychological disordercharacterized by abnormality of emotional state, including but notlimited to, depression, dysthymia, attention deficit disorder, attentiondeficit disorder with hyperactivity, bipolar disorders, bipolar andmanic conditions, and the like. The terms “attention deficit disorder”(ADD) and “attention deficit disorder with hyperactivity” (ADDH), or“attention deficit/hyperactivity disorder” (AD/HD), are used herein inaccordance with the accepted meanings as found in the Diagnostic andStatistical Manual of mental Disorders, 4^(th) Ed., American PsychiatricAssociation (1997) (DSM-IV™).

As used herein, the terms “treating or preventing depression” and“treatment and prevention of depression” mean reducing the severity ofsymptoms associated with depression which include, but are not limitedto, changes in mood, feelings of intense sadness, despair, mentalslowing, loss of concentration, pessimistic worry, agitation, andself-deprecation. Symptoms associated with depression may also bephysical symptoms, which include, but are not limited to, insomnia,anorexia, weight loss, decreased energy and libido, and abnormalhormonal circadian rhythms.

As used herein, the terms “treating or preventing a convulsive state”and “treatment and prevention of a convulsive state” mean reducing theseverity and/or frequency of symptoms associated with convulsive stateswhich include, but are not limited to, recurrent, sudden, and oftenbrief alterations of consciousness, motor activity, sensory phenomena,and autonomic responses which are often characterized by convulsiveseizures and/or tonic or clonic jerking of the extremities. The term“convulsive state” encompasses epilepsy and specific types of epilepticseizures including, but not limited to, Tonic-clonic (Grand Mal),Partial (Focal) seizures, psychomotor (Complex partial) seizures,pyknoepileptic or Absence (Petit Mal) seizure, and Myoclonic seizures.

As used herein, the terms “treating or preventing sleep disorders” and“treatment and prevention of sleep disorders” mean reducing the severityof symptoms associated with sleep disorders such as insomnia, insomniaof a primary nature with little apparent relationship to immediatesomatic or psychic events, and insomnia which is secondary to someacquired pain, anxiety or depression. Symptoms associated with sleepdisorders include, but are not limited to, difficulty in sleeping anddisturbed sleep patterns.

As used herein, the terms “treating or preventing aggressive behavior”and “treatment and prevention of aggressive behavior” mean reducing thefrequency and/or severity of manifestations of aggressive behavior whichinclude, but are not limited to, aggressive or socially inappropriatevocal outbursts and acts of physical violence.

As used herein, the terms “treating or preventing spasticity,”“treatment and prevention of spasticity,” “treating or preventingspasticity and acute muscle spasm,” and “treatment and prevention ofspasticity and acute muscle spasm” include reducing the severity ofsymptoms associated with a range of abnormalities of skeletal muscleregulation that result from problems of the nervous system. Apredominant symptom is heightened muscle tone or hyper-excitability oftonic stretch muscle reflexes. Symptoms of acute muscle spasm include,but are not limited to, trauma, inflammation, anxiety, and pain.

As used herein, the terms “treating or preventing a behavioral disorder”and “treatment and prevention of a behavioral disorder” mean reducing orrelieving from the symptoms of a behavioral disorder, which include, butare not limited to, a subjective sense of terror, a dread ofcatastrophe, uneasiness, nervousness, uncertainty, headache, fatigue,disturbed thinking, inappropriate effect, auditory hallucinations, andaggressive outbursts.

As used herein, the terms “treating or preventing a schizophrenicdisorder” and “treatment and prevention of a schizophrenic disorder”mean reducing the severity of symptoms associated with schizophrenicdisorders. Symptoms of schizophrenic disorders include, but are notlimited to, psychotic symptoms of disturbed thinking, feeling andgeneral behavior. Specific symptoms of schizophrenic disorders includethe inability to form clear, goal-directed thought, and emotionalchanges such as blunting and inappropriate affect. Other symptoms ofschizophrenic disorders include auditory hallucinations, delusions ofpersecution, threats of violence, minor aggressive outbursts, aggressivebehavior, disturbances of movement such as significant overactivity andexcitement, and retardation and stupor.

As used herein, the terms “treating or preventing a disease associatedwith abnormal plasma hormone levels” and “treatment and prevention of adisease associated with abnormal plasma hormone levels” mean reducingthe symptoms of diseases or conditions related to abnormal plasma levelsof hormones including, but not limited to, growth hormone, ACTH,prolactin, luteinizing hormone, and other adrenocortical and testicularhormones. The term “disease associated with abnormal plasma hormonelevels” encompasses endocrine disorders such as, but not limited to,growth hormone deficiency, gonadotropin deficiency, Cushing's syndrome,Grave's disease, hypothyroidism, and Addison's disease.

As used herein, the term “treating alcohol or drug addiction” meansreducing the symptoms of disease or conditions related to alcohol ordrug addiction including, but not limited to, drug or alcohol addictionor symptoms of withdrawal from alcohol or drugs. Symptoms of withdrawalinclude, but are not limited to, depression, pain, fever, restlessness,lacrimation, rhinorrhea, uncontrollable yawning, perspiration,piloerection, restless sleep, mydriasis, twitching and muscle spasms,severe aches in the back, abdomen and legs, abdominal and muscle cramps,hot and cold flashes, insomnia, nausea, vomiting, diarrhea, coryza andsevere sneezing, and increases in body temperature, blood pressure,respiratory rate, and heart rate.

SYNTHESIS AND PREPARATION

Racemic N-desmethylzopiclone is readily prepared from zopiclone using anappropriate N-dealkylation reaction. Zopiclone may be prepared accordingto the method disclosed by U.S. Pat. Nos. 3,862,149 and 4,220,646, bothof which are incorporated herein by reference. Optically pure (+) or (−)N-desmethylzopiclone can be prepared by resolution of racemicdesmethylzopiclone as described herein.

One way of preparing N-desmethylzopiclone enantiomers utilizes a chiralcarbonate, as outlined in Scheme 2:

wherein R is alkyl or vinyl. The carbonate can be resolved using certainlipases. Only one enantiomer can be prepared using this method, however,as the hydrolyzed chiral alcohol suffers a spontaneous racemization inthe reaction medium, as shown in Scheme 3:

It has thus been found that a more efficient method of producingoptically pure enantiomers of N-desmethylzopiclone (i.e.,(+)-N-desmethylzopiclone and (−)-N-desmethylzopiclone) is from zopicloneitself. Two general approaches to this method have been discovered. Inthe first, racemic zopiclone ((±)-zopiclone) is resolved to the desiredenantiomer, and the undesired enantiomer is recycled using for example abase such as, but not limited to, DBU. This is shown in Scheme 4:

According to this approach, zopiclone is resolved using methods such aschiral chromatography, although the use of one or more chiral acids,such as malic acid, mandalic acid, and DBTA, is preferred. See, e.g.,Jacques, J., et al., Enantiomers, Racemates and Resolutions,(Wiley-Interscience, New York, 1981); Wilen, S. H., et al., Tetrahedron33:2725 (1977); Eliel, E. L. Stereochemistry of Carbon Compounds(McGraw-Hill, NY, 1962); and Wilen, S. H. Tables of Resolving Agents andOptical Resolutions p. 268 (E.L. Eliel, Ed. Univ. of Notre Dame Press,Notre Dame, Ind., 1972). When preparing optically pure isomers ofzopiclone using these methods, Applicants have found that the resolutionprocess is preferably performed using higher amounts of the chiral acid.

For example, this method could be used to prepare optically pure(+)-N-desmethylzopiclone, and the (−) enantiomer in the mother liquorcould be racemized under basic conditions (e.g. with a tertiary amine)to reform (±)-zopiclone. However, since it has been discovered thatzopiclone is not very stable under these conditions and that(±)-zopiclone is thus recovered from the undesired enantiomer in lowyields, an alternative route for the recycling of the other enantiomeris outlined in Scheme 5:

A second approach of obtaining an optically pure enantiomer of zopiclonehas accordingly been developed, and is shown in Scheme 6:

wherein R is methyl. According to this method, a commercially availablealcohol precursor of zopiclone is treated with chiral auxiliary-basedchloroformate to yield one major stereoisomer of the carbonate product.Referring to Scheme 6, R* is preferably a common, inexpensive chiralalcohol such as, but not limited to menthol, or a chiral aminoalcoholsuch as, but not limited to glycinol and aminoindanol. A particularadvantage of this method is that it requires no recycling of anundesired enantiomer, yet allows recycling of the chiral auxiliary.

In another embodiment of this method, the chiral auxiliary is replacedwith an enzyme as outlined in Scheme 7:

wherein R is methyl and R′ is vinyl or 1-methylvinyl.

Another method useful in the production of optically pure(+)-N-desmethylzopiclone and optically pure (−)-N-desmethylzopiclonecomprises the use of chloroalkyl chloroformate followed by a strong baseor acid hydrolysis. See, e.g., Booher, R.N. and Pohland, A., J. Med.Chem. 20(8):1065-1068 (1977). As mentioned above, however, zopiclone andN-desmethylzopiclone tend to decompose when treated with strong base oracid. Another method comprises treating zopiclone with anazodicarboxylate and hydrolyzing the resulting product under mildconditions, as shown in Scheme 8:

According to this method, the azodicarboxylate is preferably selectedfrom the group consisting of diethyl azodicarboxylate, di-tert-butylazodicarboxylate, and di-trichloromethyl azodicarboxylate. Morepreferably, the azodicarboxylate is diethyl azodicarboxylate ordi-tert-butyl azodicarboxylate. In one embodiment, the hydrolyzing agentis a mixture of ethanol and NH₄Cl. Suitable solvents include toluene orother solvents of a secular nature.

A preferred method of preparing an optical isomer ofN-demethylzopiclone, e.g., (S)-demethylzopiclone, is illustrated inScheme 9.

According to this method optically pure (S)-zopiclone is contacted withα-chloroethyl chloroformate in a suitable solvent such as, but notlimited to, CH₃CN to form the corresponding quaternary amine salt. Seegenerally, Olofson, R. A. and Martz, T. J. J. Org. Chem., 49:2081(1984). Methanolysis of the quaternary amine salt gives thehydrochloride salt of (S)-desmethylzopiclone in high yield. Thehydrochloride salt can be isolated by filtration and the reactionby-products are removed. Purification of the crude reaction product(e.g., by recrystallization) affords pure (S)-desmethylzopiclonehydrochloride.

An advantage of this process is that methanolysis releases the productas the hydrochloride salt, which precipitates out from the reactionsystem. The isolation is straight forward, requiring simple filtration,and al reaction by-products, including CH₃Cl, CO₂, and CH₃CH(OMe)₂, arevolatile and easily removed during the process.

Yet another preferred method of preparing optically pure isomers ofN-desmethylzopiclone, e.g., (S)-desmethylzopiclone, is shown in Scheme10. According to this method racemic desmethylzopiclone is resolvedusing a suitable resolution agent such as, but not limited to,L-N-benzyloxycarbonyl phenyl alanine (L-ZPA). Racemic desmethylzopiclonecan be prepared, for example, by methods disclosed in U.S. Pat. Nos.3,862,149 and 4,220,646.

Isolation and purification of N-desmethylzopiclone is preferably doneusing chromatography, preferably column chromatography, and morepreferably high performance liquid chromatography (HPLC). Other methods,such as isolation by evaporation of the solvent, followed byrecrystallization, may also be employed.

PHARMACEUTICAL COMPOSITIONS AND METHOD OF USE

The magnitude of a prophylactic or therapeutic dose of an activeingredient of the invention (i.e., (±)-N-desmethylzopiclone, opticallypure (+)-N-desmethylzopiclone, and optically pure(+)-N-desmethylzopiclone) in the acute or chronic management of thediseases or conditions recited herein will vary with the nature andseverity of the disease or condition.

The magnitude of a prophylactic or therapeutic dose of an activeingredient of the invention (i.e., (±)-N-desmethylzopiclone, opticallypure (+)-N-desmethylzopiclone, or optically pure(−)-N-desmethylzopiclone) will also vary according to the route by whichthe active ingredient is administered. The dose, and perhaps the dosefrequency, will also vary according to the age, body weight, andresponse of the individual patient. Suitable dosing regimens can bereadily selected by those skilled in the art with due consideration ofsuch factors. In general, the recommended daily dose range for theconditions described herein lie within the range of from about 0.1 mg toabout 500 mg per day, given as a single once-a-day dose, or as divideddoses from 2 to 4 times throughout the day. Preferably, a daily doserange should be from about 0.5 mg to about 250 mg per day, morepreferably, between about 1 mg and about 200 mg per day. In managing thepatient, the therapy should be initiated at a lower dose, perhaps about0.1 mg to about 25 mg, and increased if necessary up to about 1 mg toabout 200 mg per day as either a single dose or divided doses, dependingon the patient's global response.

It may be necessary to use dosages of the active ingredient outside theranges disclosed herein in some cases, as will be apparent to those ofordinary skill in the art. Because elimination of zopiclone metabolitesfrom the bloodstream is dependant on renal and liver function, it isrecommended that the total daily dose be reduced by at least about 50%in patients with moderate hepatic impairment, and that it be reduced byabout 25% in patients with mild to moderate renal impairment. Forpatients undergoing hemodialysis, it is recommended that the total dailydose be reduced by about 5% and that the dose be withheld until thedialysis treatment is completed. Furthermore, it is noted that theclinician or treating physician will know how and when to interrupt,adjust, or terminate therapy in conjunction with individual patientresponse.

The phrase “therapeutically effective amount” as used herein withrespect to the treatment or prevention of diseases and conditionsencompasses the above described dosage amounts and dose frequencyschedules. Different therapeutically effective amounts may be applicablefor different diseases and conditions, as will be readily known by thoseof ordinary skill in the art. Similarly, amounts sufficient to treat orprevent such disorders, but insufficient to cause adverse effectsassociated with zopiclone, are also encompassed by the above describeddosage amounts and dose frequency schedules.

Any suitable route of administration may be employed for providing thepatient with an effective dosage of racemic or optically pure (+)- or(−)-N-desmethylzopiclone. Suitable routes include, but are not limitedto, oral, mucosal (e.g., nasal, sublingual, vaginal, buccal or rectal),parenteral (e.g., subcutaneous, intravenous, bolus injection,intramuscular, or intraarterial), , transdermal, and.

The pharmaceutical compositions of the invention compriseN-desmethylzopiclone, or a pharmaceutically acceptable salt, solvate,hydrate, or clathrate thereof as an active ingredient, and may alsocontain a pharmaceutically acceptable carrier and optionally othertherapeutic ingredients known to those skilled in the art. Preferredpharmaceutical compositions comprise optically pure(+)-N-desmethylzopiclone, or a pharmaceutically acceptable salt,solvate, hydrate, or clathrate thereof.

Compositions of the invention are suitable for oral, mucosal (e.g.,nasal, vaginal, or rectal), parenteral (e.g., subcutaneous, intravenous,bolus injection, intramuscular, or intraarterial), sublingual,transdermal, or buccal administration, although the most suitable routein any given case will depend on the nature and severity of thecondition being treated. The compositions may be conveniently presentedin unit dosage form and prepared by any of the methods well known in thepart of pharmacy. Dosage forms include tablets, caplets, troches,lozenges, dispersions, suspensions, suppositories, solutions, capsules,soft elastic gelatin capsules, patches, and the like. Preferred dosageforms are suitable for oral administration.

In practical use, racemic or optically pure (+)- or(−)-N-desmethylzopiclone can be combined as the active ingredient inintimate admixture with a pharmaceutically acceptable carrier accordingto conventional pharmaceutical compounding techniques. The carrier maytake a wide variety of forms and comprises a number of componentsdepending on the form of preparation desired for administration. Thecompositions of the invention include, but are not limited to,suspensions, solutions and elixirs; aerosols; or excipients, including,but not limited to, starches, sugars, microcrystalline cellulose,diluents, granulating agents, lubricants, binders, disintegratingagents, and the like. Preferably, the pharmaceutical composition is inthe form of an oral preparation.

Pharmaceutical compositions of the invention suitable for oraladministration may be presented as discrete pharmaceutical unit dosageforms, such as capsules, cachets, soft elastic gelatin capsules,tablets, caplets, or aerosols sprays, each containing a predeterminedamount of the active ingredients, as a powder or granules, or as asolution or a suspension in an aqueous liquid, a non-aqueous liquid, anoil-in-water emulsion, or a water-in-oil liquid emulsion. Suchcompositions may be prepared by any method known in the art of pharmacywhich comprises the step of bringing an active ingredient intoassociation with a carrier. In general, the compositions are prepared byuniformly and intimately admixing the active ingredients with liquidcarriers or finely divided solid carriers or both, and then, ifnecessary, shaping the product into the desired presentation. Oral solidpreparations are preferred over oral liquid preparations. Preferred oralsolid preparations are capsules and tablets.

A tablet may be prepared by compression or molding techniques.Compressed tablets may be prepared by compressing in a suitable machinethe active ingredient in a free-flowing form, such as powder orgranules, optionally mixed with one or more pharmaceutically acceptableexcipients, such as a binder, lubricant, inert diluent, granulatingagent, surface active or dispersing agent, or the like. Molded tabletsmay be made by molding, in a suitable machine, a mixture of the powderedcompound moistened with an inert liquid diluent. Preferably, eachtablet, cachet, caplet, or capsule contains from about 0.1 mg to 500 mg,more preferably from about 0.5 mg to about 250 mg, and most preferablybetween about 1 mg and about 200 mg.

Pharmaceutical compositions of the invention may also be formulated as apharmaceutical composition in a soft elastic gelatin capsule unit dosageform by using conventional methods well known in the art. See, e.g.,Ebert, Pharm. Tech, 1(5):44-50 (1977). Soft elastic gelatin capsuleshave a soft, globular gelatin shell somewhat thicker than that of hardgelatin capsules, wherein a gelatin is plasticized by the addition ofplasticizing agent, e.g., glycerin, sorbitol, or a similar polyol. Thehardness of the capsule shell may be changed by varying the type ofgelatin used and the amounts of plasticizer and water. The soft gelatinshells may contain a preservative, such as methyl- and propylparabensand sorbic acid, to prevent the growth of fungi. The active ingredientmay be dissolved or suspended in a liquid vehicle or carrier, such asvegetable or mineral oils, glycols, such as polyethylene glycol andpropylene glycol, triglycerides, surfactants, such as polysorbates, or acombination thereof.

A pharmaceutically acceptable excipient used in the compositions anddosage form of the invention may be a binder, a filler, or a mixturethereof. A pharmaceutically acceptable excipient may also include alubricant, a disintegrant, or mixtures thereof. One embodiment of theinvention encompasses a pharmaceutical composition which issubstantially free of all mono- or di-saccharide excipients. Anotherembodiment encompasses a pharmaceutical composition which is free oflactose.

Binders suitable for use in the compositions and dosage forms of theinvention include, but are not limited to, corn starch, potato starch,or other starches, gelatin, natural and synthetic gums such as acacia,sodium alginate, alginic acid, other alginates, powdered tragacanth,guar gum, cellulose and its derivatives (e.g., ethyl cellulose,cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethylcellulose), polyvinyl pyrrolidone, methyl cellulose, pre-gelatinizedstarch, hydroxypropyl methyl cellulose, (e.g., Nos. 2208, 2906, 2910),microcrystalline cellulose, or mixtures thereof.

Suitable forms of microcrystalline cellulose include, for example, thematerials sold as AVICEL-PH-101, AVICEL-PH-103 and AVICEL-PH-105(available from FMC Corporation, American Viscose Division, AvicelSales, Marcus Hook, Pa., U.S.A.). An exemplary suitable binder is amixture of microcrystalline cellulose and sodium carboxymethyl cellulosesold as AVICEL RC-581 by FMC Corporation.

Fillers suitable for use in the compositions and dosage forms of theinvention include, but are not limited to, talc, calcium carbonate(e.g., granules or powder), lactose, microcrystalline cellulose,powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol,starch, pre-gelatinized starch, or mixtures thereof.

The binder/filler in pharmaceutical compositions of the invention istypically present in about 50 to about 99 weight percent of thepharmaceutical composition.

Disintegrants are used to cause the tablet to disintegrate when exposedto an aqueous environment. Too much of a disintegrant will producetablets which may disintegrate in the bottle due to atmosphericmoisture; too little may be insufficient for disintegration to occur andmay thus alter the rate and extent of release of the drug ingredient(s)from the dosage form. Thus, a sufficient amount of disintegrant that isneither too little nor too much to detrimentally alter the release ofthe drug ingredient(s) should be used to form dosage forms of racemicand optically pure (+)- or (−)- N-desmethylzopiclone made according tothe invention. The amount of disintegrant used varies based upon thetype of formulation and mode of administration, and is readilydiscernible to those of ordinary skill in the art. Typically, about 0.5to about 15 weight percent of disintegrant, preferably about 1 to about5 weight percent of disintegrant, may be used in the pharmaceuticalcomposition.

Disintegrants suitable for use in the compositions and dosage forms ofthe invention include, but are not limited to, agar-agar, alginic acid,calcium carbonate, microcrystalline cellulose, croscarmellose sodium,crospovidone, polacrilin potassium, sodium starch glycolate, potato ortapioca starch, other starches, pre-gelatinized starch, other starches,clays, other algins, other celluloses, gums or mixtures thereof.

Lubricants suitable for use in the compositions and dosage forms of theinvention include, but are not limited to, calcium stearate, magnesiumstearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol,polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate,talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil,sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zincstearate, ethyl oleate, ethyl laurate, agar, or mixtures thereof.Additional lubricants include, for example, a syloid silica gel (AEROSIL200, manufactured by W.R. Grace Co. of Baltimore Md.), a coagulatedaerosol of synthetic silica (marketed by Deaussa Co. of Plano, Tex.),CAB-O-SIL (a pyrogenic silicon dioxide product sold by Cabot Co. ofBoston, Mass.), or mixtures thereof. A lubricant may optionally beadded, typically in an amount of less than about 1 weight percent of thepharmaceutical composition.

In addition to the common dosage forms set out above, the compounds ofthe invention may also be administered by controlled release means ordelivery devices that are well known to those of ordinary skill in theart, such as those described in U.S. Pat. Nos.: 3,845,770; 3,916,899;3,536,809; 3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767,5,120,548, 5,073,543, 5,639,476, 5,354,556, and 5,733,566, thedisclosures of which are each incorporated herein by express referencethereto. These pharmaceutical compositions can be used to provide slowor controlled-release of one or more of the active ingredients thereinusing, for example, hydropropylmethyl cellulose, other polymer matrices,gels, permeable-membranes, osmotic systems, multilayer coatings,microparticles, liposomes, microspheres, or the like, or a combinationthereof to provide the desired release profile in varying proportions.Suitable controlled-release formulations known to those of ordinaryskill in the art, including those described herein, may be readilyselected for use with the pharmaceutical compositions of the invention.Thus, single unit dosage forms suitable for oral administration, such astablets, capsules, gelcaps, caplets, and the like, that are adapted forcontrolled-release are encompassed by the invention.

All controlled-release pharmaceutical products have a common goal ofimproving drug therapy over that achieved by their non-controlledcounterparts. Ideally, the use of an optimally designedcontrolled-release preparation in medical treatment is characterized bya minimum of drug substance being employed to cure or control thecondition in a minimum amount of time. Advantages of controlled-releaseformulations may include: 1) extended activity of the drug; 2) reduceddosage frequency; and 3) increased patient compliance. In addition,controlled-release formulations can be used to effect the time of onsetof action or other characteristics, such as blood levels of the drug,and thus may affect the occurrence of side effects.

Most controlled-release formulations are designed to initially releasean amount of drug that promptly produces the desired therapeutic effect,and gradually and continually release of other amounts of drug tomaintain this level of therapeutic effect over an extended period oftime. In order to maintain this constant level of drug in the body, thedrug must be released from the dosage form at a rate that will replacethe amount of drug being metabolized and excreted from the body.

The controlled-release of an active ingredient may be stimulated byvarious inducers, for example pH, temperature, enzymes, water, or otherphysiological conditions or compounds. The term “controlled-releasecomponent” in the context of the invention is defined herein as acompound or compounds, including, but not limited to, polymers, polymermatrices, gels, permeable membranes, liposomes, microspheres, or thelike, or a combination thereof, that facilitates the controlled-releaseof the active ingredient.

Pharmaceutical compositions of the invention may also be formulated forparenteral administration by injection (e.g., subcutaneous, intravenous,bolus injection, intramuscular, or intraarterial), and may be dispensedin a unit dosage form, such as a multidose container or an ampule. Suchcompositions for parenteral administration may be in the form ofsuspensions, solutions, emulsions, or the like in aqueous-or oilyvehicles, and in addition to the active ingredients may contain one ormore formulary agents, such as dispersing agents, suspending agents,stabilizing agents, preservatives, and the like.

The invention is further defined by reference to the following examplesdescribing in detail the preparation of the compositions of theinvention. It will be apparent to those skilled in the art that manymodifications, both to materials and methods, may be practiced withoutdeparting from the purpose and interest of this invention.

EXAMPLES Synthesis of N-desmethylzopiclone

Racemic and optically pure enantiomers of N-desmethylzopiclone wereprepared according to the procedures provided below. It should be notedthat X-ray crystal diffraction studies indicate that the absoluteconfiguration of both (+)-zopiclone and (+)-N-desmethylzopiclone is theS-configuration.

Example 1

Synthesis of (±)-N-desmethylzopiclone

To a solution of (±)zopiclone (6.2 g, 20 mmol) in toluene (120 ml) wasadded diethyl azodicarboxylate (DEAD, 8.2 g, 50.0 mmol) and the solutionwas stirred at 60° C. for 26 hours. The solvent was removed underreduced pressure. The residue was added to 60 ml of EtOH/NH₄Cl aq (1:1)and the resulting mixture was refluxed for 4 hours. The reaction mixturewas concentrated to remove ethanol under reduced pressure and theresidue was partitioned by adding saturated NaHCO₃ solution and CH₂Cl₂(100 ml). The organic phase was then separated and washed with water (30ml), brine (30 ml), and dried over Na₂SO₄. The crude product was loadedonto a silica gel column and eluted with CH₃CN:MeOH:NH₄OH (25:4:1) togive 1.56 g of product with chemical purity of approximately 91% (25%yield). A second flash chromatography yielded (±)-N-desmethylzopiclonewith >98% chemical purity. ¹H NMR (CDCl₃), δ: 2.4-3.8 (b, 8H), 7.7-7.82(dd, 1H), 8.0 (s, 1H), 8.4 (s,1H), 8.5 (d, 1H), 8.82-8.88 (dd, 2H), 2-6(NH). ¹³C NMR δ45.5, 45.9, 79.3, 116.3, 128.5, 138.3, 144.1, 146.9,148.0, 153.7, 155.8, 163.2.

Example 2

Synthesis of (+)-zopiclone

(a) Preparation of (+)-zopiclone-D-malate salt:

A three-neck 2.0 L flask was charged with (±)-zopiclone (40 g, 0.101mol, 1.0 eq), D-malic acid (13.4 g, 0.97 eq.), 406 mL MeOH and 754 mLacetone. The reaction mixture was heated in an oil bath to 55-56 ° C.for about 30 min and gradually cooled to 45-47 ° C. over approximately30 mn. (+)-zopiclone-D-malate seeds (0.lg, 0.02%) was added at 45-47°C.The reaction mixture was cooled to 40° C. over 1 h and then cooled to10-15° C. over 3 h. Then the slurry was held at 10-15° C. for 30 min.The solid product was isolated by filtration and washed with cold MeOH(2×50 mL, 0-5° C.). The white product was dried at 30-40° C./28 mmHgover 6-12 h to give (+)-Zopiclone-D-malate (22.6 g, 42 %, 96.5 % ee).

(b) Preparation of (+)-zopiclone:

A three-neck 250 mL flask was charged with (+)-zopiclone-D-malate (10 g,93% ee), 20 mL water and 150 mL of EtOAc. The reaction mixture washeated in an oil bath to 30-40° C. An aqueous K₂CO₃ solution (40%, 8 g)was added slowly over 5 min. The mixture was then heated to 60-65° C.and the organic phase was isolated and washed with 100 mL water. Themixture was polish filtered, rinsed with EtOAc (20 mL) and concentratedto 70-80 mL. The resulting slurry was cooled and held for 2 h at 0-5 °C. The crystal product was isolated by filtration and was washed withcold EtOAc (20 mL, 0-5 ° C.). The white product was dried at 30-40°C./28 mmHg over 6-12 h to give (+)-zopiclone (6.4 g, 86.2%, 99.9% ee).

Example 3

Synthesis of (+)-N-desmethylzopiclone

To a solution of (+)-zopiclone (4.0 g, 10.3 mmol) in toluene (100 ml)was added DEAD (5.4 g, 30.0 mmol) and the solution was stirred at 55° C.for 40 hours. The solvent was removed under reduced pressure and theresidue was added 60 ml of EtOH/NH₄Cl aq (1:1) and the resulting mixturewas refluxed for 4 hours. The reaction mixture was concentrated underreduced pressure to remove the ethanol and the residue was partitionedby adding saturated NaHCO₃ solution and CH₂C 1₂ (100 ml). The organicphase was then washed with water (30ml), brine (30 ml), and dried overNa₂SO₄. The crude product was loaded onto a silica gel column and elutedwith CH₃CN:MeOH:NH₄OH (25:4: 1) to give 1.25 g of the product withchemical purity of ca 90% (27% yield). A second flash chromatographyyielded (+)-N-desmethylzopiclone with >97% chemical purity and >99% eeby chiral HPLC: Chiralcel OD, mobile phase: Hexane:Ethanol:Methanol:DEA(55:15:30:0.1). Retention time: 11.6 minutes for the (+) isomer and 14.7minutes for (−) isomer. ([α]=+141 C=1, CDCl₃), ¹H NMR (CDCl₃), δ2.4-3.8(b, 8H), 7.7-7.82(dd, 1H), 8.0 (s, 1H), 8.4 (s, 1H), 8.5 (d, 1H),8.82-8.88 (dd, 2H), 2-6 (NH). ¹³C NMR δ: 45.5, 45.9, 79.3, 116.3, 128.5,138.3, 144.1, 146.9, 148.0, 153.7, 155.8, 163.2.

Example 4

Synthesis of (−)-N-desmethylzopiclone

(−)-Desmethylzopiclone was prepared from (−)-zopiclone according to theprocedure described above. ([α]=−158, C=1, CDl₃), ¹H NMR (CDCl₃), δ:2.4-3.8 (b, 8H), 7.7-7.82 (dd, 1H), 8.0 (s, 1H), 8.4 (s, 1H), 8.5 (d,1H), 8.82-8.88 (dd, 2H), 2-6 (NH). ¹³C NMR, δ: 45.5, 45.9, 79.3, 116.3,128.5, 138.3, 144.1, 146.9, 148.0, 153.7, 155.8, 163.2.

Example 5

Preparation of (+)-desmethylzopiclone hydrochloride

(a) Demethylation:

To a 12 L reaction flask under Ar, were charged (+)-zopiclone (778 g,2.0 mmol), ACN (4L) and 1-chloroethyl chloroformate (328.9 g, 2.3 mol).The reaction mixture was heated at 73-75° C. for 6 h with stirring. MeOH(1.0 L) was added and the mixture was 10 heated under a reflux for 3-4h. The reaction slurry was cooled to 5-10° C. for 2 h. The solid productwas isolated via filtration, followed by washing with EtOH (200 mL×3)and toluene (200 mL×3). The final product was dried in an oven for 12 h(28 mm Hg) at 40-45° C. The isolated product (i.e., crude(+)-desmethylzopiclone hydrochloride salt) was 610 g (74%).

(b) Recrystallization of (+)-desmethylzopiclone hydrochloride (DMZ):

To a 12 L reaction flask equipped with overhead stirrer under argon,were charged crude (+)-DMZ.HCl salt (450 g), EtOH (4.8 L) and water (1.5L). The reaction mixture was heated under reflux for 1 h, and thencooled to 20° C. over 1 h. The resulting slurry was 20 further cooled to0-5° C. and stirred at that temperature for 1 h. The white solid productwas isolated by filtration followed by washing with EtOH (500 mL). Thefinal product was dried in an oven for 12 h (28 mm Hg) at 40-45° C. Theisolated product was 377 g (84%). ^(1H NMR ()300 MHZ, DMSO), δ (ppm):8.95 (dd, 2H, J =7.2, 3.0 Hz),), 8.57 (d, 1H, J=7.2 Hz), 8.45 (s, 1H),8.10 (s, 1H), 7.80 (m, 1H), 3.60 (bro d, 2H), 3.25 (bro s, 2H), 2.88(bro s, 2H), 2.62 (bro s, 2H). MS 374 (M+).

The process was repeated and the results from both experiments aresummarized in Table 1 below.

TABLE 1 Recrystallization² Demethylation¹ Purity (HPLC Experiment Yield(%) HPLC A % Yield (%) assay %) 1 610 g(74) 99.74 377 g(84) 99.5 2 580g(71) 99.34 485 g(86) 99.5 ¹Using (+)-zopiclone (ee>99%) prepared inaccordance with Example 2. ²Partial crude product was used for therecrystallization

Example 6

Resolution of racemic desmethylzopiclone

This is an alternate method of preparing of optically pure(+)-desmethylzopiclone. Racemic desmethylzopiclone can be obtainedeither by the chloroformate demethylation method described in Example 5above using racemic zopiclone as the starting material, or by knownliterature methods.

(a) Identifying Resolution Agents:

A reagent screen was performed to identify an effective resolution agentfor racemic N-desmethylzopiclone. The screen identifiedL-N-benzyloxycarbonyl phenyl alanine (L-ZPA) (available from SEMchemical) as an effective resolution agent for desmethylzopiclone andindicated that other acids suitable for resolution of zopiclone areineffective for the resolution of N-desmethylzopiclone. L-ZPA may alsobe used for the resolution of racemic zopiclone. Table 2 summarizes theexperimental results.

TABLE 2 (±)- Desmethyl- Acid Comments Exp. # zopiclone (g) (g) SolventsConditions and Yields 1 1.0 L-ZPA 40 70 mL 1.75-79° C. 1 h 80% ee, 0.8(1eq.) EtOH/7 mL 2. rt. for 2 h 33% yield water 2 10 L-ZPA EtOH/water1.75-79° C. 1 h 80% ee, 30.8(1 eq.) 2. rt. for 4 h 28% yield 3 8.0 L-ZPAEtOH/water 1.75-79° C. 1 h 91% ee, 6.15(1 eq.) 2. rt. for 12 h 31.4%yield 4 1.0 D-malic acid 20 mL 1.75-79° C. 1 h No crystals 0.36(1 eq.)EtOH/2 mL 2. rt. for 14 h observed. water 5 1.0 D-malic acid 20 mL1.75-79° C. 1 h No crystals 0.36(1 eq.) MeOH/2 mL 2. rt. for 12 hobserved. water 6 1.0 D-DTTA 50 mL 1.75-79° C. 1 h 1. at room 1.0(1 eq.)EtOH/5 mL 2. rt. for 2 h with 80% water ee. 2. Hold it for 1 h, 0% ee. 71.0 D-DTTA 50 mL 1.75-79° C. 1 h Filtered at 1.0(1 eq.) EtOH/5 mL 2.79°C. for 5 50° C. with water min. 15% yield and 95.5% ee. 8 32 L-ZPA 1600mL 1.75-79° C. 1 h 27.6% yield, 1.0 eq. EtOH/160 2. rt. for 14 h 96% eemL water 3. reslurry in EtOH

Using L-ZPA, and a solvent mixture of EtOH and water highly opticallyenriched (typical>90% ee) (+)-desmethylzopiclone.L-ZPA salt wasisolated. The free base of (+)-desmethylzopiclone can be obtained by thetreatment of (+)-desmethylzopiclone.L-ZPA salt in EtOAc with K₂CO₃solution.

(b) Resolution of (±)-Desmethylzopiclone:

(±)-Desmethylzopiclone (8.0 g, 21.3 mmol) and 6.4 g L-ZPA (21.3, 1equiv.) were combined in 40 mL water and 400 mL EtOH. The mixture washeated to 75-78° C. for 1 h to form a clear solution. The mixture wascooled to 20° C. overnight. The solids were isolated and the cake waswashed with 150 mL EtOH. The wet cake was transferred into a 500 mLflask with 150 mL EtOH. The slurry was refluxed for 2 h. The slurry wascooled to 0-5° C. for 1 h. The solid product was isolated via filtrationand was washed with EtOH (25 mL). The final product was dried in an ovenfor 12 h (28 mm Hg) at 45-50° C. to give (+)-desmethylzopiclone-L-ZPAsalt (4.5 g, 31.4%, 91% ee).

Example 7

Determination of biological activity

A pharmacologic study is conducted to determine the relative potency,comparative efficacy, and binding affinity of N-desmethylzopiclone. Thepharmacologic profile of hypnotic-sedative, anxiolytic agents of thebenzodiazepine class is well established, and has been extended tonon-benzodiazepine agents of the cyclopyrrolone class. See, e.g.,Goodman & Gilman's The Pharmacological Basis of Therapeutics, Hardman,J. G., et al., eds. ch. 17, pp. 361-396 (9¹h ed., 1996); Bardone, M. C.,et al., Abstract No. 2319, 7^(th) Int. Congr. Pharm. Paris, (July, 1978:Pergamon Press, London); Julou, L. et al, Pharmacology, Biochemistry andBehavior, 23:653-659 (1985).

A variety of experimental models can be used to characterize the variousactivities of N-desmethylzopiclone, including its anticonvulsant,myorelaxant, anti-aggressive, sedative-hypnotic, and anxiolytic (i.e.,anti-anxiety) activities. In an examination of each element of thepharmacologic profile, N-desmethylzopiclone is compared withpharmacologic standards such as nitrazepam and diazepam in a variety ofanimal models. The dose (mg/kg) of each agent that is capable ofinhibiting by 50% (the ID₅₀ or ED₅₀) an induced response in rodents, forexample, provides the basis for comparison. Pentylenetetrazole-induced,picrotoxin convulsions, and electrically-induced convulsions can thus beused to demonstrate the anti-convulsant activity ofN-desmethylzopiclone. Haefely, W., Psychotropic Agents, Hofmeister, F.and Stille, G., eds., part 11, pp. 12-262 (Springer Verlag, Berlin:1981). Further, in the rat, in the amygdala kindled model of epilepsy,daily electrical stimulation of the amygdala induces a progressiveincrease of epileptic after discharge duration, with increasingepileptic behavioral symptoms, producing in about two weeks ageneralized convulsive crisis. Presumably, previously ineffectivestimuli have sensitized neuronal pathways, and it has been suggestedthat a similar mechanism may exist for the induction of an anxiety statein man after repeated stresses.

Similar models are available for determination of the myorelaxant,anti-aggressive, and sedative-hypnotic activities ofN-desmethylzopiclone in both mice and rats. See, Julou, L. et al.,Pharmacology, Biochemistry and Behavior, 23:653-659 (1985).

The pharmacologic activity of N-desmethylzopiclone may also be comparedwith benzodiazepines for its affinity for binding to both CNS andperipheral benzodiazepine receptors. In this biochemical affinitybinding study, the binding of ³H-radiolabeled N-desmethylzopiclone isstudied in a synaptosomal membrane preparation of cerebral tissue fromfemale rat brain. The tissue is preferably prepared by homogenization inice-cold isosmotic (0.32 M) sucrose, and centrifugation, first at lowspeed (1,000×g for 10 minutes), with the resultant supernatant solutionthen being centrifuged at high speed (48,000×g for 20 minutes). Theresulting pellet is suspended in Kreb-Tris buffer at pH 7.4, and theconcentration of protein is adjusted to 15 mg/ml. This synaptosomalmembrane preparation may be stored at −18° C. until used at roomtemperature (e.g., about 22° C.) with the radio-cyclopyrrolone inKreb-Tris buffer solution pH 7.4. Following a 30-minute incubation,separation of the bound and free drug is performed by centrifugation at1,000×g for 10 minutes in scintillation vials. The supernatant solutionis collected, the pellet is dissolved in a counting vehicle, and theradioactivity is counted using a liquid scintillation counter. Theoriginal supernatant solution from the first incubation, which containsunbound radiolabeled drug, may be used in additional binding studiesusing the same method. Additional controls involve, for instance, studyof the radioactivity bound in the presence of 10 μM flunitrazepam (abenzodiazepine), which experiment is useful in assessing non-specificbinding. Furthermore, the binding of various concentrations ofradiolabeled N-desmethylzopiclone in the presence of a fixedconcentration of GABA provides additional information as to themodulation of the GABA-ergic system by N-desmethylzopiclone. See,Jacqmin, P., et al, Arch. Int. Pharmacodyn, 282:26-32 (1986); Jacqmin,P., etal., J. Pharm. Belg. 40:35-54 (1985). With regard to peripheralbenzodiazepine receptors and their distinction from centralbenzodiazepine binding sites, see, e.g., Verma, A. and Snyder, S. H.,Ann. Rev. Pharmacol. Toxicol. 29:307-322 (1989), which is herebyincorporated by reference.

Example 8

Measured biological activity

The binding of N-desmethylzopiclone was determined at the centralbenzodiazepine receptor and at the non-selective muscarinic receptor,both of which were isolated from rat cerebral cortex. Compounds weretested initially at 10 μM in duplicate, and if at least a 50% inhibitionof specific binding was observed, they were tested further at 10different concentrations in duplicate in order to obtain fullcompetition curves. IC₅₀ values (concentration required to inhibit 50%specific binding) were determined by nonlinear regression analysis ofthe curves, and inhibition constants (K_(i)) were also calculated. Thesedata are provided below in Table 3.

TABLE 3 Benzodiazepine Muscarinic Compound IC₅₀ and (K_(i)) Values (nM)(% Inhibition) (±)-N-desmethylzopiclone 1,100 10 (924)(+)-N-desmethylzopiclone 545 19 (458) (−)-N-desmethylzopiclone 7,090 24(5,960) Diazepam 12 not determined (10)

Racemic and optically pure enantiomers of N-desmethylzopiclone clearlyhave affinity for the benzodiazepine site. Advantageously, and asdiscussed above, these compounds exhibited little activity at themuscarinic receptor.

Example 9

Oral formulation

Suitable ingredients of a tablet dosage form of (+)-N-desmethylzopicloneare provided in Table 4.

TABLE 4 Component Quantity per Tablet (mg) (+)-N-desmethylzopiclone 75Lactose 125 Corn Starch 5.0 Water (per thousand tablets) 30.0 ml*Magnesium Stearate 0.5 *The water evaporates during manufacture.

The active ingredient (i.e., (+)-N-desmethylzopiclone) is blended withthe lactose until a uniform blend is formed. The smaller quantity ofcorn starch is blended with a suitable quantity of water to form a cornstarch paste. This is then mixed with the uniform blend until a uniformwet mass is formed. The remaining corn starch is added to the resultingwet mass and mixed until uniform granules are obtained. The granules arethen screened through a suitable milling machine, using a ¼ inchstainless steel screen. The milled granules are then dried in a suitabledrying oven until the desired moisture content is obtained. The driedgranules are then milled through a suitable milling machine using ¼ meshstainless steel screen. The magnesium stearate is then blended and theresulting mixture is compressed into tablets of desired shape,thickness, hardness and disintegration. Tablets may be coated bystandard aqueous or nonaqueous techniques.

Another tablet dosage formulation suitable for use with an activeingredient of the invention is provided by Table 5:

TABLE 5 Quantity per Tablet (mg) Component Formula A Formula B Formula C(+)-N-desmethylzopiclone 20 40 100 Lactose BP 134.5 114.5 309.0 StarchBP 30 30 60 Pregelatinized Maize Starch BP 15 15 30 Magnesium Stearate0.5 0.5 1.0 Compression Weight 200 200 500

The active ingredient is sieved and blended with lactose, starch, andpregelatinized maize starch. Suitable volumes of purified water areadded and the powders are granulated. After drying, the granules arescreened and blended with the magnesium stearate. The granules are thencompressed into tablets using punches.

Tablets of other strengths may be prepared by altering the ratio ofactive ingredient to pharmaceutically acceptable carrier, thecompression weight, or by using different punches.

Example 10

Oral formulation

Capsules of (±)-N-desmethylzopiclone may be made using the ingredientsprovided in Table 6:

TABLE 6 Capsule Unit Dosage Forms Quantity per Capsule (mg) FormulationA B C (±)-N-desmethylzopiclone 50.0 100.0 200.0 Lactose 48.5 148.5 48.5Titanium Dioxide 0.5 0.5 0.5 Magnesium Stearate 1.0 1.0 1.0 Fill Weight100.0 250.0 250.0

The active ingredient (i.e., (±)-N-desmethylzopiclone) is sieved andblended with the excipients. The mixture is filled into suitably sizedtwo-piece hard gelatin capsules using suitable machinery. Other dosesmay be prepared by altering the ratio of the active ingredient (e.g.,(±)-N-desmethylzopiclone) and pharmaceutically acceptable carrier, thefill weight and, if necessary, by changing the capsule size to suit.

Example 11

Oral Formulation

Hard gelatin capsules of (+)-N-desmethylzopiclone may be made using theingredients provided in Table 7:

TABLE 7 Hard Gelatin Capsule Unit Dosage Forms 0.1 mg capsule (amount 5mg capsule 20 mg capsule Component in mg) (amount in mg) (amount in mg)(±)-N-desmethylzopiclone 0.1 5.0 20.0 Microcrystalline 90.0 90.0 90.0Cellulose Pre-gelatinized 102.7 97.8 82.8 Starch Croscarimellose 7.0 7.07.0 Magnesium Stearate 0.2 0.2 0.2

The active ingredient is sieved and blended with the excipients listed.The mixture is filled into suitably sized two-piece hard gelatincapsules using suitable machinery and methods well known in the art.See, e.g., Remington's Pharmaceutical Sciences, 16th or 18th Editions,each incorporated herein. Other doses may be prepared by altering thefill weight and, if necessary, changing the capsule size to suit. Any ofthe stable, non-lactose hard gelatin capsule formulations above may beformed.

Example 12

Oral formulation

Compressed tablet formulations of (±)-N-desmethylzopiclone may be madeusing the ingredients provided in Table 8:

TABLE 8 Compressed Tablet Formulations 0.1 mg capsule (amount 5 mgtablet 20 mg tablet Component in mg) (amount in mg) (amount in mg)(±)-N-desmethylzopiclone 0.1 5.0 20.0 Microcrystalline 90.0 90.0 90.0Cellulose Pregelatinized 102.7 97.8 82.8 Starch Croscarmellose 7.0 7.07.0 Magnesium Stearate 0.2 0.2 0.2

The active ingredient is sieved through a suitable sieve and blendedwith the non-lactose excipients until a uniform blend is formed. The dryblend is screened and blended with the magnesium stearate. The resultingpowder blend is then compressed into tablets of desired shape and size.Tablets of other strengths may be prepared by altering the ratio of theactive ingredient (i.e., (±)-N-desmethylzopiclone) to the excipient(s)or modifying the tablet weight.

The embodiments of the invention described above are intended to bemerely exemplary, and those skilled in the art will recognize, or beable to ascertain using no more than routine experimentation, numerousequivalents to the specific procedures described herein. All suchequivalents are considered to be within the scope of the invention andare encompassed by the following claims.

What is claimed is:
 1. A method of treating or preventing alcohol ordrug addiction in a patient, which comprises administering to a patientsuffering from alcohol or drug addiction a therapeutically orprophylactically effective amount of N-desmethylzopiclone, or apharmaceutically acceptable salt, solvate, hydrate, or clathratethereof.
 2. The method of claim 1 wherein the N-desmethylzopiclone isracemic.
 3. The method of claim 1 wherein the N-desmethylzopiclone is(+)-N-desmethylzopiclone, substantially free of its (−) enantiomer. 4.The method of claim 1 wherein the N-desmethylzopiclone is(−)-N-desmethylzopiclone, substantially free of its (+) enantiomer. 5.The method of claim 1 wherein the therapeutically or prophylacticallyeffective amount of N-desmethylzopiclone or pharmaceutically acceptablesalt, solvate, hydrate, or clathrate thereof is from about 0.1 mg toabout 500 mg.